Despite evidence of a substantial genetic component, the inherited biological factors that underlie human life span (longevity) remain unknown. Our main hypothesis is that unique genotypes and phenotypes protect against age-related diseases to assure exceptional healthy longevity. In the past 14 years we recruited our discovery cohort of the Longevity Genes Project (LGP), and obtained significant genetic data supporting the hypothesis for protective genotypes in centenarians compared with unrelated controls. We then tested this hypothesis in a second independent NIH funded LonGenity study (P01 AG027734), which recruited: (i) offspring of parents of exceptional longevity (OPEL-LonGenity) and (ii) offspring of parents who had usual survival (OPUS-LonGenity). The subjects in LGP and LonGenity cohorts are Ashkenazi Jewish adults (AJs) who are relatively homogenous genetically and in their social-economic status, lending strength to genetic discovery. The LonGenity study demonstrated that the OPEL phenotype and associated longevity genotypes were successfully linked to improved cardiovascular, metabolic, and cognitive health in aging. We now propose to extend our study to the frailty phenotype, building on exciting new preliminary data obtained with pilot funding from the American Federation of Aging Research that links exceptional longevity phenotypes and genotypes to physical function and frailty. The term frailty is used clinically as a global concept to describe a condition, common in older adults, of impaired strength, endurance, and balance, vulnerability to trauma and other stressors, and high risk for morbidity, disability, and mortality. Our goal is to evaluate the roleof exceptional longevity trait and genotypes in decreasing risk of developing frailty and age-related declines in its important physical function constituents such as gait, balance, and strength in 1400 older adults in the LonGenity study. This proposal will be jointly directed by Dr. Verghese, an expert in frailty, gait disorders and dementia, and Dr. Barzilai, PI of the LonGenity study and a world renowned geneticist. The following three aims are proposed. 1. Study the role of family history of longevity on reducing risk of physical decline and frailty in aging. 2. Determine the role of longevity related genetic factors in reducing risk of physical decline and frailty in agingas well as examine the interplay between longevity and frailty- associated genotypes and validate the findings in 3 external cohorts. 3. Examine the effect of biological exposures (protein products of established longevity genes, their relevant intermediates and vascular biomarkers) on the association between exceptional longevity and longitudinal change in physical function in aging. We base our new project on the research infrastructure, strong interdisciplinary collaborations, unique population, genetic discoveries, and scientific foundation laid by the LonGenity study. If distinct genetic and biological changes can be shown to contribute to the prevention of frailty, it may be possible to develop and test interventions to prevent frailty and physical function decline that may provide additional benefits beyond those obtained from treatments from currently recognized diseases.